Objectives Increased blood leukocytes are associated with all-cause mortality and death from coronary disease and cancer in the general population. Limited information is available in people with HIV. Methods We analyzed blood leukocytes in 1850 participants of the Swiss HIV Cohort Study who died (2000–2023) and 1850 matched controls (median age at death 52 years, 77% male, 77% with suppressed HIV RNA on antiretroviral therapy). We assessed uni-/multivariable odds ratios (OR) for all-cause mortality, considering major clinical and HIV-related mortality risk factors, leukocytes measured >1 year before death (primary analysis) and in the latest available blood sample, and potential confounders for leukocytes. Results Leukocytes showed a U-shaped association with mortality. At a median of 433 (interquartile range [IQR], 396–495) days before death, multivariable-adjusted OR for death in the highest (leukocytes ≥7730/μL) vs. middle quintile (leukocytes 5290–6260/μL) was 1.56 (95% confidence interval, 1.20–2.02). Multivariable-adjusted OR in the lowest (leukocytes ≤4250/μL) vs. middle leukocyte quintile was 1.51 (1.14–2.01). For comparison, death-OR for hypertension, diabetes and current smoking were 1.27 (1.06–1.53), 1.91 (1.41–2.57), and 2.72 (2.14–3.45), respectively. Leukocytosis was uncommon (cases, 4.4% vs. controls, 2.3%; p = 0.004). The effect size of the highest leukocyte quintile increased in the latest blood sample (median 86 [IQR], 43–152 days before death; OR=1.99 [1.44–2.76]). High leukocytes were associated with death from non-AIDS/non-hepatic cancer, cardiovascular, and respiratory causes. Low leukocytes were associated with liver-related death. Conclusions High leukocytes, measured >1 year before death and mostly within the normal range, are independently associated with mortality in people with HIV in Switzerland.